Vasopressor Properties of Nitric Oxide Synthase Inhibitor T1059. Part I: Synthesis, Toxicity, NOS-Inhibition Activity, and Hemodynamic Effects Under Normotensive Conditions

Compound T1059 (1-cyclohexanecarbonyl-2-ethylisothiourea hydrobromide) was found to be water soluble, moderately toxic (i.p. LD 16 and LD 50 of 274 and 380 mg/kg), and capable of competitively inhibiting nitric-oxide synthase (NOS) activity with significant selectivity toward inducible and endotheli...

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Bibliographic Details
Published in:Pharmaceutical chemistry journal 2018-07, Vol.52 (4), p.294-298
Main Authors: Filimonova, M. V., Shevchenko, L. I., Makarchuk, V. M., Chesnakova, E. A., Surinova, V. I., Shevchuk, A. S., Filimonov, A. S., Kryzhanovskii, S. A., Shevchenko, T. F., Bugrova, A. E., Kalamkarov, G. R.
Format: Article
Language:English
Subjects:
Analysis
Endothelium
Medicine
Nitric oxide
Organic Chemistry
Pharmacology/Toxicology
Pharmacy
Toxicity
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Summary:Compound T1059 (1-cyclohexanecarbonyl-2-ethylisothiourea hydrobromide) was found to be water soluble, moderately toxic (i.p. LD 16 and LD 50 of 274 and 380 mg/kg), and capable of competitively inhibiting nitric-oxide synthase (NOS) activity with significant selectivity toward inducible and endothelial isoforms (IC 50 for nNOS, iNOS, and eNOS of 60.3, 1.8, and 3.2 μM, respectively). T1059 was rapidly absorbed after a single i.p. injection (dose range 10 – 30 mg/kg) and distributed in tissues, causing pronounced suppression of endogenous NO production. T1059 at a dose of 10 mg/kg in normotensive anesthetized Wistar rats produced long-term vasoconstriction. The observed changes in vascular tone did not influence inotropic heart function but were accompanied by weak bradycardia.
ISSN:0091-150X
1573-9031
DOI:10.1007/s11094-018-1809-2